WO2005003149A1 - Process for the preparation of finasteride form i - Google Patents
Process for the preparation of finasteride form i Download PDFInfo
- Publication number
- WO2005003149A1 WO2005003149A1 PCT/GB2004/002906 GB2004002906W WO2005003149A1 WO 2005003149 A1 WO2005003149 A1 WO 2005003149A1 GB 2004002906 W GB2004002906 W GB 2004002906W WO 2005003149 A1 WO2005003149 A1 WO 2005003149A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- finasteride
- process according
- finasteride form
- addition
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
Definitions
- the present invention is concerned with an improved process for the preparation of finasteride Form I, finasteride Form I prepared by the process of the present invention, pharmaceutical compositions including the same, therapeutic uses thereof and methods of treatment employing the same.
- 5-alpha reductase is an enzyme associated with the nuclear membrane and it is found in high concentrations in the human male reproductive tissues, skin and liver. 5-alpha reductase catalyses the conversion of testosterone to dihydrotestosterone (DHT).
- DHT dihydrotestosterone
- Two isoenzymes (type I and II) of 5-alpha reductase have been identified in the human tissue. The type I isoenzyme is found in scalp skin, while the type II isoenzyme is found in the prostrate.
- Type I 5-alpha reductase is responsible for approximately one third of circulating DHT and type II 5-alpha reductase is responsible for about the remaining two thirds of the circulating DHT.
- the balding scalp contains miniaturized hair follicles and increased amounts of DHT compared to hairy scalp.
- Finasteride, 17 ⁇ -(N-t-butyl carbamoyl)-4-aza-5-alpha-androst-l-ene-3-one, is a potent inhibitor of the type II 5-alpha reductase.
- Finasteride selectively blocks the production of dihydrotestosterone by competitive inhibition of 5-alpha reductase, resulting in significant decreases in serum and tissue DHT concentrations. Finasteride produces a rapid reduction in serum DHT concentration, reaching 65% suppression within 24 hours of oral dosing with a lmg tablet.
- Various prior art disclosures provide for different processes for producing and isolating finasteride Form I, by using different organic solvents, or a mixture of protic and aprotic solvents.
- US Patent 4760071 discloses a process for the preparation of 17 ⁇ -(N-monosubstituted carbamoyl)-4-aza-5-alpha-androst-l-ene-3-one, pharmaceutical compositions useful in inhibiting testosterone 5-alpha reductase, and methods of treating hyperandrogenic conditions using the same, particularly benign prostatic hyperplasia.
- US Patent 5652365 discloses a process for producing finasteride Form I, which comprises crystallising a solution of finasteride in a water immiscible organic solvent, optionally comprising water, so as to obtain solvated and non-solvated finasteride in solution.
- the amount of organic solvent and water in the solution is sufficient to cause the solubility of the non-solvated form of finasteride to be exceeded.
- the non-solvated form of finasteride is less soluble than any other form of finasteride in the organic solvent and water solution.
- the process further comprises recovering the resultant solid phase and removing the solvent.
- the organic solvent is ethyl acetate or isopropyl acetate and the amount of water in the solvent mixture is below 4mg/ml.
- US Patent 5886184 discloses a process for producing finasteride which comprises reacting the magnesium halide salt of 17 ⁇ - carboalkoxy-4-aza-5-alpha-androst-l-ene-3-one with t-butylamino magnesium halide, present in at least a 2:1 molar ratio to the ester, formed from t-butyl amine and an aliphatic magnesium halide at ambient temperature in an inert organic solvent under an inert atmosphere followed by heating and recovering the product finasteride as polymorphic crystalline Forms I and II.
- US Patent Application 20020042425A1 discloses an invention that involves a method of treating and / or reversing androgenic alopecia and promoting hair growth, and methods of treating acne vulgaris, seborrhoea, and female hirsutism, by administering to a patient in need of such treatment a 5-alpha reductase II inhibitor, such as finasteride, in a dosage amount of less than 5mg/day.
- the invention further provides a process to finasteride, employing a solvent such as glacial acetic acid.
- US Patent 5670643 discloses a process of preparing finasteride by reacting an acid chloride with t-butylamine in an aprotic solvent, e.g.
- pyridine toluene, methylene chloride, dimethylformamide or acetonitrile
- a base e.g. pyridine, diisopropylethylamine, dimethylaminopyridine, or triethylamine
- Salts such as LiCl and iBr can be used to facilitate this reaction.
- the resulting compound can be purified by known techniques, such as chromatography and crystallisation.
- finasteride Form I is obtained from solvents, or mixtures of solvents, such as tetrahydrofuran, glacial acetic acid, ethyl acetate, toluene and / or isopropyl acetate.
- solvents such as tetrahydrofuran, glacial acetic acid, ethyl acetate, toluene and / or isopropyl acetate.
- solvents or mixtures of solvents, such as tetrahydrofuran, glacial acetic acid, ethyl acetate, toluene and / or isopropyl acetate.
- solvents such as tetrahydrofuran, glacial acetic acid, ethyl acetate, toluene and / or isopropyl acetate.
- solvents such as tetrahydrofuran, glacial acetic acid, ethyl acetate, toluene
- replacing the solvent with the non-solvent comprises distilling off the solvent followed by addition of the non-solvent
- a process according to the present invention comprises the steps of: (i) dissolving finasteride in a solvent to form a solution; (ii) distilling off the solvent from the solution obtained in step (i); (iii) adding a non-solvent to the product of step (ii); and (iv) isolating finasteride Form I.
- the finasteride is initially dissolved in a solvent such as methanol or dichloromethane, and the dissolution may be carried out at a temperature in the range of ambient to reflux, as appropriate.
- the resulting solution of finasteride in the solvent may optionally be clarified using decolourising agents.
- a non-solvent as employed in a process according to the present invention typically comprises a poor solvent for finasteride and as such, when added to a solution or slurry comprising finasteride, results in precipitation thereof.
- the non-solvent is water.
- the non-solvent is an organic solvent in which the solubility of finasteride in not more than about 5%w/v, or 1 in 20 at the boiling point thereof.
- the organic non- solvent may be selected from straight chain or branched alkanes, such as hexane, heptane or octane, or aromatic solvents, such as toluene or xylene, or esters such as isobutyl acetate or isopropyl acetate.
- distillation is continued following addition of the non-solvent.
- a process according to the present invention further comprises stirring a precipitated product obtained further to addition of the non-solvent for a period sufficient to obtain finasteride Form I, for example for a period sufficient to transform finasteride to finasteride Form I.
- a preferred process according to the present invention can, therefore, comprises dissolving finasteride in a solvent, replacing the solvent partially or substantially completely with a non-solvent, stirring a precipitated product obtained further to addition of the non-solvent and thereafter isolating finasteride Form I.
- the finasteride starting material employed in a process according to the present invention comprises finasteride as prepared by processes known in the art, for example as described in the basic finasteride patent US 4760071 substantially as hereinbefore described.
- the present invention further provides finasteride Form I prepared by a process according to the present invention substantially as hereinbefore described.
- Finasteride Form I as provided by the present invention comprises substantially pure finasteride Form I, and is substantially free of associated impurities.
- finasteride Form I having a purity of at least about 99.6%w/w, more preferably at least about 99.7%w/w and in certain embodiments at least about 99.8%w/w.
- the present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of finasteride Form I as provided according to the present invention, together, with one or more pharmaceutically acceptable carriers, diluents or excipients therefor.
- pharmaceutically acceptable it is meant that the carrier, diluent or excipient must be compatible with finasteride Form I as provided according to the present invention, and not be deleterious to a recipient thereof.
- the pharmaceutical compositions or medicaments are prepared in a manner well known in the pharmaceutical art.
- compositions according to the present invention may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solutions, suspensions or the like.
- compositions as provided by the present invention comprise oral dosage forms selected from the group consisting of tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, solutions, suspensions, syrups and emulsions.
- a pharmaceutical composition according to the present invention comprises isolated substantially pure polymorphic Form I of finasteride.
- a composition according to the present invention is suitably substantially equivalent to 1 mg to 500 mg of finasteride.
- the present invention provides a process for preparing finasteride tablets for oral administration, which tablets are film-coated tablets containing 1 mg or 5 mg of finasteride.
- finasteride Form I Conventional methods are employed in mixing finasteride Form I with inactive ingredients, such as intra-granular ingredients (for example, lactose monohydrate, sodium starch glycolate and starch), binder (for example, starch, lactose monohydrate and purified water), extra-granular ingredients (for example, colloidal silicon dioxide, sodium benzoate, sodium starch glycolate and magnesium stearate), and coating the tablet by using coating agents such as opadry 04F50702 blue and purified water.
- intra-granular ingredients for example, lactose monohydrate, sodium starch glycolate and starch
- binder for example, starch, lactose monohydrate and purified water
- extra-granular ingredients for example, colloidal silicon dioxide, sodium benzoate, sodium starch glycolate and magnesium stearate
- coating agents such as opadry 04F50702 blue and purified water.
- Finasteride Form I as provided by the present invention has therapeutic utility as a 5- alpha reductase inhibitor, for example in the treatment of acne vulgaris, seborrhea, female hirsutism, androgenic alopecia which includes female and male pattern baldness, and in particular benign prostatic hyperplasia.
- the present invention further provides a method of inhibiting 5-alpha reductase in a patient in need thereof comprising administering to said patient an effective inhibitory amount of finasteride Form I as provided according to the present invention.
- the present invention also provides use of finasteride Form I as provided according to the present invention in the manufacture of a medicament for inhibiting 5-alpha reductase.
- the present invention is illustrated below with reference to the following Examples.
- Example 1 Dichloromethane (150L) and finasteride (11kg) were charged to a reactor and stirred to dissolve. Dichloromethane was distilled out and water (120L) was added and the distillation was continued until the vapour temperature reached about 80°C. The contents were cooled to ambient and stirred for 24-30 hours and the product was filtered and washed with water and dried under vacuum to obtain finasteride Form I having purity of about 99.7%.
- Examgle 2 Methanol (170L) and finasteride (10kg) were charged to a reactor, and neutral alumina (1kg) and activated charcoal (1kg) were added and stirred for 15 minutes at a temperature of 25-35°C and filtered.
- Example 3 Dichloromethane (150L) and finasteride (11kg) were charged to a reactor. Neutral alumina (1kg) and activated charcoal (1kg) were added and stirred for 15 minutes at a temperature of 25-35°C and filtered. The filtrate was transferred to another reactor and dichloromethane was distilled out until a thick slurry was obtained. Isopropyl acetate (80L) was added and the distillation was continued until the vapour temperature reached about 80°C. The product was filtered hot and washed with isopropyl acetate and dried under vacuum at 80°C to obtain finasteride Form I having a purity of about 99.8%.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Steroid Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE602004016170T DE602004016170D1 (en) | 2003-07-03 | 2004-07-05 | PROCESS FOR PREPARING FINASTERIDE FORM I |
US10/563,138 US7550593B2 (en) | 2003-07-03 | 2004-07-05 | Process for the preparation of finasteride Form I |
EP04743251A EP1651661B1 (en) | 2003-07-03 | 2004-07-05 | Process for the preparation of finasteride form i |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN676/MUM/2003 | 2003-07-03 | ||
IN676MU2003 | 2003-07-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2005003149A1 true WO2005003149A1 (en) | 2005-01-13 |
Family
ID=33561923
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2004/002906 WO2005003149A1 (en) | 2003-07-03 | 2004-07-05 | Process for the preparation of finasteride form i |
Country Status (5)
Country | Link |
---|---|
US (1) | US7550593B2 (en) |
EP (1) | EP1651661B1 (en) |
AT (1) | ATE406376T1 (en) |
DE (1) | DE602004016170D1 (en) |
WO (1) | WO2005003149A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8299015B2 (en) | 2006-07-25 | 2012-10-30 | Lipoxen Technologies Limited | Derivatisation of granulocyte colony-stimulating factor |
US10188739B2 (en) | 2014-02-27 | 2019-01-29 | Xenetic Biosciences, Inc. | Compositions and methods for administering insulin or insulin-like protein to the brain |
WO2020099513A1 (en) | 2018-11-13 | 2020-05-22 | Lipoxen Technologies Limited | Glycopolysialylation of blinatumomab |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013124865A1 (en) | 2012-02-21 | 2013-08-29 | Sujoy Kumar Guha | Drug delivery system for finasteride to prostate |
CN111896658B (en) * | 2020-08-10 | 2022-10-04 | 扬子江药业集团四川海蓉药业有限公司 | Method for detecting isomer impurities in finasteride by using high performance liquid chromatograph |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4760071A (en) * | 1984-02-27 | 1988-07-26 | Merck & Co., Inc. | 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors |
EP0599376A2 (en) * | 1992-11-19 | 1994-06-01 | Merck & Co. Inc. | A process for the production of finasteride |
WO2001032683A1 (en) * | 1999-11-01 | 2001-05-10 | Torcan Chemical Ltd. | Production of polymorphic forms i and ii of finasteride by complexation with group i or ii metal salts |
WO2002020553A1 (en) * | 2000-09-07 | 2002-03-14 | Dr. Reddy's Laboratories Ltd. | NOVEL POLYMORPHIC FORM OF 17-β-(N-TER.BUTYL CARBAMOYL)-4-AZA-5-α-ANDROST-1-EN-3-ONE AND A PROCESS FOR PREPARING IT |
US20020042425A1 (en) * | 1993-10-15 | 2002-04-11 | Gormley Glenn J. | Transdermal treatment with 5-alpha reductase inhibitors |
WO2004039828A1 (en) * | 2002-10-31 | 2004-05-13 | Ragactives, S.L. | Method of obtaining polymorphic form i of finasteride |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5670643A (en) * | 1995-03-16 | 1997-09-23 | Glaxo Wellcome Inc. | Method for preparing finasteride |
-
2004
- 2004-07-05 US US10/563,138 patent/US7550593B2/en not_active Expired - Fee Related
- 2004-07-05 WO PCT/GB2004/002906 patent/WO2005003149A1/en active IP Right Grant
- 2004-07-05 EP EP04743251A patent/EP1651661B1/en not_active Not-in-force
- 2004-07-05 DE DE602004016170T patent/DE602004016170D1/en active Active
- 2004-07-05 AT AT04743251T patent/ATE406376T1/en not_active IP Right Cessation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4760071A (en) * | 1984-02-27 | 1988-07-26 | Merck & Co., Inc. | 17β-N-monosubstituted carbamoyl-4-aza-5α-androst-1-en-3-ones which are active as testosterone 5α-reductase inhibitors |
EP0599376A2 (en) * | 1992-11-19 | 1994-06-01 | Merck & Co. Inc. | A process for the production of finasteride |
US20020042425A1 (en) * | 1993-10-15 | 2002-04-11 | Gormley Glenn J. | Transdermal treatment with 5-alpha reductase inhibitors |
WO2001032683A1 (en) * | 1999-11-01 | 2001-05-10 | Torcan Chemical Ltd. | Production of polymorphic forms i and ii of finasteride by complexation with group i or ii metal salts |
WO2002020553A1 (en) * | 2000-09-07 | 2002-03-14 | Dr. Reddy's Laboratories Ltd. | NOVEL POLYMORPHIC FORM OF 17-β-(N-TER.BUTYL CARBAMOYL)-4-AZA-5-α-ANDROST-1-EN-3-ONE AND A PROCESS FOR PREPARING IT |
WO2004039828A1 (en) * | 2002-10-31 | 2004-05-13 | Ragactives, S.L. | Method of obtaining polymorphic form i of finasteride |
Non-Patent Citations (1)
Title |
---|
WAWRZYCKA I ET AL: "STRUCTURAL CHARACTERIZATION OF POLYMORPHS AND MOLECULAR COMPLEXES OF FINASTERIDE", JOURNAL OF MOLECULAR STRUCTURE, ELSEVIER, AMSTERDAM, NL, vol. 474, 1999, pages 157 - 166, XP000920855, ISSN: 0022-2860 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9492556B2 (en) | 2006-07-25 | 2016-11-15 | Lipoxen Technologies Limited | N-terminal derivatisation of proteins with polysaccharides |
US8394921B2 (en) | 2006-07-25 | 2013-03-12 | Lipoxen Technologies Limited | N-terminal derivatisation of proteins with polysaccharides |
EP2630972A2 (en) | 2006-07-25 | 2013-08-28 | Lipoxen Technologies Limited | N-terminal polysialylation |
US8981050B2 (en) | 2006-07-25 | 2015-03-17 | Lipoxen Technologies Limited | N-terminal derivatisation of proteins with polysaccharides |
US9040478B2 (en) | 2006-07-25 | 2015-05-26 | Lipoxen Technologies Limited | Derivatisation of granulocyte colony-stimulating factor |
US9474805B2 (en) | 2006-07-25 | 2016-10-25 | Lipoxen Technologies Limited | Derivatisation of granulocyte colony-stimulating factor |
US8299015B2 (en) | 2006-07-25 | 2012-10-30 | Lipoxen Technologies Limited | Derivatisation of granulocyte colony-stimulating factor |
US9492557B2 (en) | 2006-07-25 | 2016-11-15 | Lipoxen Technologies Limited | Derivatisation of granulocyte colony-stimulating factor |
US9789163B2 (en) | 2006-07-25 | 2017-10-17 | Lipoxen Technologies Limited | N-terminal derivatisation of proteins with polysaccharides |
EP3299033A1 (en) | 2006-07-25 | 2018-03-28 | Lipoxen Technologies Limited | N-terminal polysialylation |
US10300144B2 (en) | 2006-07-25 | 2019-05-28 | Lipoxen Technologies Limited | N-terminal polysialylation |
US10188739B2 (en) | 2014-02-27 | 2019-01-29 | Xenetic Biosciences, Inc. | Compositions and methods for administering insulin or insulin-like protein to the brain |
WO2020099513A1 (en) | 2018-11-13 | 2020-05-22 | Lipoxen Technologies Limited | Glycopolysialylation of blinatumomab |
Also Published As
Publication number | Publication date |
---|---|
US20070021455A1 (en) | 2007-01-25 |
ATE406376T1 (en) | 2008-09-15 |
DE602004016170D1 (en) | 2008-10-09 |
EP1651661A1 (en) | 2006-05-03 |
EP1651661B1 (en) | 2008-08-27 |
US7550593B2 (en) | 2009-06-23 |
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